Unraveling the genetic architecture of cochleovestibular malformations

揭示耳蜗前庭畸形的遗传结构

• 批准号: 10522114
• 负责人: Isabelle Veerle Suzanne Schrauwen
• 金额: $ 42.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522114
• 关键词: Affect; African; Anatomy; Belgium; Bilateral; Candidate Disease Gene; Cells; Child; Child Development; Cities; Clinical; Cochlea; Cochlear Nerve; Collaborations; Collection; Complex; Counseling; Country; DNA; Data; Data Set; Databases; Defect; Developed Countries; Development; Diagnosis; Diagnostic; Disease; Ear; Enrollment; Epithelial; Ethnic Origin; Ethnic group; Etiology; Event; Family; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Hispanic; Hispanic Populations; Hospitals; Human; Imaging Techniques; In Situ Hybridization; Individual; Intervention; Knowledge; Labyrinth; Magnetic Resonance Imaging; Methods; Mexico; Modeling; Molecular; Molecular Diagnosis; Molecular Diagnostic Testing; Nerve; Neural Crest; New York City; Newborn Infant; Not Hispanic or Latino; Otolaryngologist; Parents; Pathogenicity; Patients; Phenotype; Population; Population Heterogeneity; RNA analysis; Repetitive Sequence; Research; Resolution; Resources; Sensorineural Hearing Loss; Sensory; Site; South Asian; Temporal bone structure; Therapeutic; Therapeutic Intervention; United States; Variant; Washington; Work; X-Ray Computed Tomography; base; bone imaging; causal variant; cohort; congenital hearing loss; cost effective; craniofacial; dark matter; de novo mutation; demographics; diagnostic screening; diagnostic tool; ethnic diversity; ethnic health disparity; exome; exome sequencing; experimental study; genetic architecture; genetic variant; genome sequencing; genomic data; genomic variation; health disparity; hearing impairment; improved; inner ear development; innovation; insight; malformation; molecular diagnostics; negative affect; neurosensory; novel; novel therapeutic intervention; outcome prediction; personalized medicine; phenotypic data; preference; proband; racial and ethnic; racial diversity; racial population; recruit; repository; screening; sound; therapeutic development; transcriptome sequencing

SUMMARY Hearing impairment is a common and disabling sensory defect which in a subset of individuals can be due to an abnormal cochleovestibular anatomy. Cochleovestibular (CV) and cochleovestibular nerve (CVN) anomalies can significantly impact a child’s development and currently pose challenges in treatment and management. Little research has been done to understand the etiology of these malformations, especially those that are non- syndromic and severe, such as cochlear aplasia. There is a crucial need to better understand the underlying molecular mechanisms of these conditions to aid in diagnosis, intervention and management. In addition, health disparities exist in the molecular diagnosis and treatment of hearing impairment (HI) in Hispanics, as the molecular etiology of HI has been scarcely studied in this ethnic group. It is imperative to study the etiology of CV/CVN anomalies in diverse racial/ethnic populations to understand which genes/variants are a frequent cause of this disorder in each population. Molecular diagnostics and treatment can therefore be tailored based on population-specific information. We hypothesize that a significant subset of severe non-syndromic CV/CVN anomalies has a genetic etiology, which may differ between populations, and knowledge of this information will improve our understanding of inner ear development. Our preliminary research suggests that rare genetic variants, including de novo variants, are implicated in the development of severe CV/CVN anomalies. Our proposal leverages genomics data and temporal bone imaging data to unravel the molecular basis of non-syndromic CV/CVN malformations. To achieve this, we will 1) recruit and establish a large genomic database of racially/ethnically diverse families with CV/CVN malformations which have been phenotyped in detail. 2) Next, we will determine the genetic spectrum of underlying variation implicated in CV/CVN malformations in both Hispanic and non-Hispanic individuals. 3) Last, using recruited and existing cohorts of individuals with CV/CVN malformations and prelingual sensorineural hearing impairment, we will identify novel causal genes implicated in CV/CVN malformations and assess their expression during early craniofacial and inner ear development. We have assembled a team that has the collective expertise to achieve these aims as well as a prior track record of productive collaboration. This work will elucidate the genetic architecture of severe non-syndromic CV/CVN malformations diverse ethnic/racial populations and improve our basic knowledge of human inner ear development and the mechanisms leading to abnormal development. This knowledge can then be used to improve molecular diagnostics, guide therapeutic intervention and management, predict outcomes, and develop novel therapeutic approaches benefiting individuals of diverse ethnicity/racial background.

概括 听力障碍是一种常见的致残性感觉缺陷，在一部分人中可能是由于 耳蜗前庭解剖结构异常可导致耳蜗前庭 (CV) 和耳蜗前庭神经 (CVN) 异常。 严重影响儿童的发育，目前对治疗和管理构成挑战。 已经进行了研究来了解这些畸形的病因，特别是那些非 综合症和严重的，如耳蜗发育不全，迫切需要更好地了解潜在的症状。 这些疾病的分子机制有助于诊断、干预和管理。 西班牙裔听力障碍 (HI) 的分子诊断和治疗存在差异，因为 该族群HI的分子病因学研究甚少，因此研究其病因势在必行。 不同种族/民族人群中的 CV/CVN 异常，以了解哪些基因/变异是常见原因 因此，可以根据每个人群的情况来制定这种疾病的分子诊断和治疗。 特定人群的信息。 我们发现，严重非综合征性 CV/CVN 异常的一个重要子集具有遗传病因， 不同人群之间可能有所不同，了解这些信息将提高我们对内在的理解 我们的初步研究表明，罕见的遗传变异，包括从头变异，是存在的。 涉及严重 CV/CVN 异常的发展，我们的建议利用了基因组学数据和 颞骨成像数据揭示非综合征性 CV/CVN 畸形的分子基础。 为此，我们将 1) 招募并建立一个包含 CV/CVN 的种族/族裔多样化家庭的大型基因组数据库 2）接下来，我们将确定其遗传谱。 与西班牙裔和非西班牙裔个体的 CV/CVN 畸形有关的潜在变异 3) 最后， 使用招募的和现有的 CV/CVN 畸形和语前感音神经个体队列 听力障碍，我们将识别与 CV/CVN 畸形相关的新致病基因并评估其 早期颅面和内耳发育过程中的表达。 我们组建了一支团队，拥有实现这些目标的集体专业知识以及之前的业绩记录 这项工作将阐明严重非综合征 CV/CVN 的遗传结构。 畸形不同民族/种族人群并提高我们对人类内耳的基础知识 然后可以使用这些知识来了解发育和导致异常发育的机制。 改善分子诊断、指导治疗干预和管理、预测结果并开发 新颖的治疗方法使不同种族/种族背景的个体受益。